Archive for December, 2013

Big Theory

It could explain the Chronic Fatigue Initiatives pathogen study results. It could show how an infection could cause chronic fatigue syndrome, and then seemingly disappear. It integrates two of the biggest players in ME/CFS; the autonomic nervous system and the immune system. It focuses on the herpesviruses. It includes sensory nerves, an increasingly hot topic in ME/CFS/FM, and it follows an established model of fibromyalgia.

If it’s correct VanElzakker’s hypothesis could explain a lot about chronic fatigue syndrome

Created by Michael VanElzakker, a Tufts neuroscientist, the VNIH proposes that nerve loving viruses trigger a difficult to detect immune response which produces the fatigue and other symptoms present in chronic fatigue syndrome.

Location, Location, Location

VanElzakker proposes that an infection triggers ME/CFS, but if his theory is right the most important thing about that infection is not what it is but where it is. That ‘where’ is the biggest nerve in the body; the vagus nerve – a ‘wandering nerve’ that stretches over much of our torso and sends its roots into most of the organs of the body.

The vagus nerve isn’t just any nerve; it’s the nervous system’s immune conduit to the brain. VE believes that an infection there doesn’t need to be large to cause havoc in the brain; it just needs to be present.

In some ways, vagus nerve appears, in fact, to be ripe for infection in ME/CFS. As it ‘wanders’ through the body it comes into contact with virus havens such as the esophagus, stomach, lungs and spleen, all of which have likely at one time or another harbored the herpesviruses (HHV6, HHV-5 [cytomegalovirus], HHV-4 [Epstein-Barr virus]) that have been thought to be associated with ME/CFS for decades.

Most humans carry several of these herpesviruses in latent form unless some stressor or biological event allows them to become reactivated.

VanElzakker believes that upon reactivation these viruses replicate and move outside the nerves where they run into glial cells that attempt to gobble them up. The glial cells perk up remarkably in the presence of viruses, releasing all manner of pro-inflammatory and neuroexcitatory compounds (proinflammatory cytokines [IL-1B, IL-6, TNF-a], glutamate, prostaglandins, nitric oxide and free radicals. )

Receptors on the vagus nerve that sniff out these alarm signals tell the brain an infection is present, which then shuts the body down by sending out signals (fatigue, flu-like symptoms, pain, etc.) that slow the body down, tell it to stop moving, stop eating, stop thinking.

Because these infections are localized right on the main immune conduit to the brain, VanElzakker believes they don’t need to produce the outsized cytokine response researchers have been looking for. All they need to do is tweak the vagus nerve and let it and the brain the do the rest.

You don’t need a ‘big’ infection to produce ME/CFS; all you need is a little infection in the right place.

The Key Component – Glial Cells

The glial cells that surround and protect the vagus nerve are the key. Once thought to be mere structural scaffolding for the nerves, these cells (e.g., astrocytes) are now known to regulate nervous system signaling, a fact that’s been borne out in chronic fatigue syndrome’s sister disease, fibromyalgia.

VE believes pathogen triggered,but localized immune system activation around the vagus nerves may be causing ME/CFS

Glial cell release of cytokines, glutamate, free radicals, etc. in the dorsal horn of the spinal cord causes increased pain sensitivity and allodynia in susceptible individuals. At some point the constant production of these excitatory substances causes a switch to get flipped sending the pain response spiraling upwards instead of shutting down.

At its most extreme (allodynia), the nervous system can interpret even the slightest touch as eliciting pain. The pain response system at this point, as VanElzakker, puts it, has become, ‘pathological’.

That model of pain production has been solidly documented. VanElzakker proposes the same process causing pain sensitization in the dorsal horn is causing fatigue and other symptoms in chronic fatigue syndrome, except this time it’s associated with glial cells surrounding the vagus nerve.

A New Model of Fatigue

There is no reason to suspect that vagus-nerve associated glia would function any different than pain associated glia. VanElzakker

Nobody knows what a herpesvirus infection of the vagus nerve would look like, but VanElzakker doesn’t see any reason it should look any different from an infection in other parts of the body.

We know a herpesvirus infection of your trigeminal nerve gets you shingles and chronic pain. Researchers believe a chronic infection in the dorsal horn of your spinal cord will can get you fibromyalgia and allodynia. Would an infection of the vagus nerve get you sickness behavior and chronic fatigue syndrome?

There’s a good chance it might. Animal studies indicate that fatigue/flu-like symptoms go gangbusters when the vagus nerve gets infected. In fact, it’s possible the flu-like symptoms associated with infections wouldn’t even exist without the vagus nerve. Rodents with their vagus nerves cut don’t act sick even after they’ve been infected with a pathogen; the fevers, fatigue, the desire for isolation – are gone.

What if the vagus nerve receptors were…ceaselessly bombarded with these cytokines? The symptoms of sickness behavior would be severe and intractable.

If the glial cells surrounding the vagus nerve function the same way they do in the dorsal horn, a lingering or even a ‘smoldering’ infection (aka Dr. Lerner’s theory), could trigger the similar type of hypersensitive reaction in the vagus nerve. In this ‘immune sensitization’ model, it takes only very small amounts of cytokines to trigger fatigue and flu-like behavior.

In fact, VanElzakker suggests chronic fatigue syndrome and fibromyalgia could both be ‘glial cell diseases’.

How to Have an Infection That Doesn’t Show Up in the Blood

“Cytokines Responding to a Local Infection Stay Local” VanElzakker

If VanElzakker is right, the same group of viruses are wreaking havoc in different locations in different ME/CFS patients. The problem is it’s just darn hard to get at them. You can’t find them in the blood and you sure as heck can’t biopsy the vagus nerve.

A series of fascinating studies exploring how central nervous system infections cause chronic nerve pain may, however, illuminate what’s happening in ME/CFS. First, researchers mimicked a localized nervous system infection by dropping an HIV protein known to activate glial cells into rodents’ spinal cord.

The vagus nerve is the immune conduit to the brain; mice studies suggest it plays a key role in producing ‘sickness behavior’

They found that the glial cells reared up and starting producing pro-inflammatory cytokines to take care of the intruder. Not surprisingly, the rodents looked and acted sick – the cytokines were doing their job to keep the animal down and isolated – but no trace of those cytokines could be found in their bloodstream. Only if the animal’s spinal cord was sampled near where the ‘infection’ was it possible to find any evidence of increased cytokine levels.

If VanElzakker is right, then blood cytokine levels in ME/CFS are a function of where your vagus nerve is infected. If it’s infected in your abdominal area, you might find cytokines in the blood, but it might be hard to find them in your spinal fluid. If your vagus nerve is infected near your brainstem you might find cytokines in the spinal fluid, but you probably won’t find them in your blood.

Wherever the infection is there’s a good chance you may not find cytokines in the blood at all. This isn’t a completely surprising fact or even restricted to the vagus nerve infections; cytokines in mice with lung infections, for instance, showed up only when the lungs themselves were sampled.

Next Steps

VanElzakker suggests animal studies to better understand infections of the vagus nerve and to ultimately to build a chronic fatigue syndrome rodent model would be helpful. Magnetic resonance imaging (MRI) may be able to detect viral lesions in central nervous system tissues. It is not yet known if PET scans can detect the activation of a different type of glial cells; the satellite glia that are in vagus nerve ganglia and paraganglia, but special PET scans might be able to be used to assess microglial activation.

Cadaver studies of people who had ME/CFS definitely aren’t his first choice, but they could find activated glia, inflammation and viral infections of the vagus nerve and associated structures. Finally, novel protocols should be developed to assess the vagus nerve and brainstem functioning in ME/CFS. The severely ill should be given a prominent place in future studies.

If VanElzakker is correct different treatments could be in store for people with ME/CFS

A New Treatment Approach

Glial Cell Inhibitors

If VE’s theory is correct then glial cell inhibitors to stop the immune activation, antivirals to attack the pathogens, vagus nerve stimulation and surgical alteration of the vagus nerve might be possible treatments sometime in the future.

Glial cell inhibitors have a good safety profile, have been helpful at curbing neuropathic pain and are not used much in chronic fatigue syndrome or fibromyalgia.

If VanElzakker is right then Ibudilast, a drug in clinical trials now for another disorder, is a possibility.

Ibudilast (AV411/MN166), a drug used mostly in Japan, knocks down glial cell activation by inhibiting the production of a proflammatory cytokine called macrophage-migration-inhibitory factor (MIF) and TNF-a. Reduced levels of TNF-a could provide a bonus by increasing the breakdown of a excitatory neurotransmitter called glutamate that may be helping to keep your central nervous system on edge.

Ibudilast is also known to have neuroprotective and vasodilative effects and is usually used to treat asthma and stroke. It’s ability to suppress glial cell activation has made it useful in the treatment of neuropathic pain, and it’s currently undergoing clinical trials to treat neuropathic pain in Australia. Ibudilast can also prevent viral activation of the microglia.

Other general microglial inhibitors exist (minocyline, pentoxyfilline, propentfylline) but have undesirable side effects.

Antivirals

Stopping glial cell activation may be easier than getting at the viruses themselves. Herpesviruses living in the sensory ganglia may be protected from antiviral drugs and antibodies. (One new herpesvirus drug may be coming on the market soon, however.) Alternately, viruses other than the herpesviruses could be infecting the vagus nerve.

Behavioral Therapy

VanElzakker also notes that while behavioral therapies are not curative and may only apply to a subset of patients, they can help moderate symptoms and improve quality of life in some.

Conclusion

The VNIT may be able to explain more puzzling aspects of chronic fatigue syndrome than any other. Next up we talk with Dr. VanElzakker about how he got interested in ME/CFS and what his theory may mean for this disorder.

A New Approach to Fibromyalgia

Infections are a common trigger for fibromyalgia (FM), and fibromyalgia patients are experience many ‘sickness behavior’ symptoms, but we haven’t usually associated FM with viruses or immune system problems.

So it’s going to be Fibromyalgia that gets the really big antiviral trial ….

That’s been changing recently. A immune biomarker has been proposed. Small fiber neuropathy – possibly caused by immune dysregulation – has been found. Dr. Dantini has been treating FM with antivirals for years. The immune system’s starting to get some respect in FM.

Last year we heard that Dr. William Pridgen in Alabama was getting his ducks in a row for a major antiviral trial. Four weeks ago in an email exchange he confirmed that the money – $3.3 million dollars – all gathered from ‘angel investors’ is in hand, and the four-month 143 patient trial began in early October.

A Different Path

The pathways researchers and doctors take to get to disorders like FM or chronic fatigue syndrome are nothing but diverse, and it’s worth taking a look at how Dr. Pridgen, a surgeon, came to fibromyalgia. (Dr. Julia Newton’s pathway to ME/CFS was through elderly people experiencing dizziness and, to her surprise, a great deal of fatigue.) Dr. Pridgen’s pathway to fibromyalgia was through the gut.

Pridgen saw a pattern emerge in his treatment of thousands of patients with chronic gastrointestinal issues that intrigued him. A patient would get better, but then experience a stressful event that would send him/her back into the soup. They would get better, but during the next relapse they would stay sick longer and their recovery period would be shorter. Eventually they would be sick all the time.

Shorter and shorter relapses over time in his patients lead Pridgen to conclude that a virus must be involved.

The problem, he thought, had to be some sort of pathogen that was steadily increasing with every recurrence. Giving his patients antivirals helped, but problems remained. Then he found that adding an anti-inflammatory (which also had anti-viral properties) reduced their fatigue, gastrointestinal complaints, depression and anxiety markedly and improved their energy.

An observational study indicating that the combination drug approach had a 90% ‘efficacy rate’ led Pridgen to start a company, enlist investors and create the large treatment trial.

Pridgen’s theory fits glove and hand with several other fibromyalgia/chronic fatigue syndrome theories. As with Van Elzakkers’ vagus nerve infection theory for ME/CFS, Pridgen’s theory begins with a nerve loving virus that takes up residence – for life – in nerves in the sensory ganglia found across the body.

Instead of HHV6 or EBV Pridgen believes herpes simplex viruses, are the key in FM/ME/CFS. Other than a 1993 theory proposing herpes simplex virus was at play in ME/CFS, interest has been scanty. HSV-1’s ability to affect many of the genes and gene pathways suspected of playing a role in nervous system disorders such as Alzheimer’s, Parkinson’s, depression, chronic fatigue syndrome and autism, however, lead one researcher to propose it could play a role in all of them.

HSV-1 has been found in the esophagus, stomach and duodenum of the gastrointestinal system. In fact, HSV-1 was proposed to cause ‘recurrent functional gastrointestinal disorders’ such as IBS, as far back as 1996.

Pridgen’s patent application indicates that he believes that stressors and peptides and hormones released by the sympathetic nervous system and HPA axis set the stage for herpes simplex-1 reactivation. Pridgen proposes that repeated HSV reactivation can kill the sensory nerve cells ( small fiber neuropathy?) and destroy part of the nerve ganglion. (Stress induced HSV-1 reactivation has been documented in laboratory animal studies.)

Once these neurons and ganglia are damaged, Pridgen believes they send out signals that ultimately muck up the pain processing centers in the central nervous system. The over-generation of neurotransmitters such as glutamate, Substance P, serotonin, norepinephrine, dopamine, brain-derived neurotrophic factor (BDNF) involved in this process then causes central sensitization.

Antiviral Plus

Pridgen proposes to stop the viral reactivation and the central sensitization with antivirals; an approach that’s been tried before in chronic fatigue syndrome, but not in the way Pridgen’s doing it.

Are two ‘antivirals’ better than one? We’ll find out sometime next year.

One of Pridgen’s patent applications suggests that one of his unique insights has been to combine valacyclovir (valtrex) with an anti-inflammatory, Celecoxib (Celebrex) that has antiviral properties. Other combinations are being tested and Pridgen stated they have not released the make-up of IMC formulation used in the trial. It’s not clear, then, what drugs at what doses were used in the study or which will prove most effective.

Pridgen proposes that the two drugs hit the virus at different stages of its life-cycle. Pummeling the virus with that one-two punch, he believes, will finally stop the virus from reactivating.

Pridgen and Duffy are looking for herpes simplex virus, but other herpes viruses could be affected by this treatment. We won’t know if they are until further studies are done.

Inflammation Gone Awry

Pridgen and his partner, molecular virologist, Carol Duffy will also attempt to develop a diagnostic test for fibromyalgia using cytokine arrays they believe will document high levels of pro-inflammatory cytokines and low levels of anti-inflammatory cytokines.

Like VanElzakker, Pridgen believes the body is over-reacting to the virus.

“It’s basically exaggerating its reaction to the virus. Any little stress reactivates the virus, and, rather than the body saying, ‘Oh, this is just a virus I’ve been living with this since I was five,’ the body keeps saying, ‘Oh, my God,’ and throws on all this inflammation, and that gives these people this pain.”

“There is a theory that all pain, one way or another, is inflammation,” Duffy says. “It’s inflammation gone awry.”

Celebrex – The Antiviral?

We don’t hear anything about Celecoxib as a virus fighter in ME/CFS, but some evidence suggests it could be efficacious against herpes simplex virus. The ability of COX-2 inhibitors to decrease prostaglandin production is believed to push the immune system towards a Th1 (antiviral) response and away from the Th2 response often found in ME/CFS.

Pridgen believes Celexicob’s antiviral properties, in concert with Valtrex, will knock down the herpes viruses causing FM and ME/CFS

Celebrex was shown to reduce stress induced herpes virus reactivation in the nervous systems of mice. Another study found that reactivation of HSV-1 in mice was associated with upregulation of COX-2 gene expression in their nerve ganglia. HHV-6 can also induce COX-2 expression. Both COX-1 and COX-2 are needed for viral replication.

(One mother found that VIOXX (now off the market) reduced her daughters IL-6 levels and eliminated the ‘panic attacks’ she’d experienced following a central nervous system infection.)

(Aspirin and flavanoids, vitamin E and fish oils also inhibit COX-2. The efficacy some ME/CFS patients experience from using omega-3 fatty acids could be due to antiviral effects.)

Tissue Biopsies

Along with treating the virus, Pridgen and his partner, molecular virologist Carol Duffy, will be using PCR to test for the virus, not in the blood, but in gut tissue samples.

One of the most intriguing aspects of the Pridgen-Duffy study is the search for HSV-1, not in the blood, but in the tissues. We know the Chronic Fatigue Initiative’s Pathogen study failed to find evidence of viral infection in the blood. Now, Pridgen and Duffy are testing gut samples for herpes virus simplex in their study.

First PCR will be used to search for herpesviruses in both the control and FM gut samples. Then antibodies will be used to determine if an active infection is present. In subsequent studies, electron microscopy will look for the herpesviruses particles themselves.

In preliminary studies 18/19 fibromyalgia patients with gut issues contained herpes simplex virus DNA in their gut tissues. No other herpesviruses were found. Immunoblot testing indicated that an active infection was present in eight of nine positive biopises.

Dr. Pridgen reported in an email they are still trying to determine the optimum doses and cautioned everyone to wait until the results of the phase three trial are done before starting this treatment. He also stated he feels they are ‘very close’ to helping many people with this condition. The results of trial will be released mid-year, 2014.

Conclusion

A successful trial could usher in a new era of treatment for fibromyalgia and perhaps chronic fatigue syndrome

Pridgen and Duffy’s big multi-center antiviral trial in Fibromyalgia is nothing if not exciting in its scope and approach. Pridgen’s ability to come up with over $3,000,000 in startup funding suggests he and Duffy have got some solid data backing their trial up. .

If they results are positive, Pridgen and Duffy could usher in an entirely new way of treating both fibromyalgia and chronic fatigue syndrome.

The more specific requirements of the ICC however, may select patients that are less clinically diverse. This could improve detection of immunological findings in CFS/ME.

Study authors.

How much of a difference the International Consensus Criteria (or any definition) makes is a major question in chronic fatigue syndrome.

Dr. Sonya Marshall-Gradisnik’s team in Australia, who just celebrated the grand opening of the National Centre for Neuroimmune and Emerging Diseases at Griffith Univeristy, examines this question in a recent study. Dr. Marshall is a leading ME/CFS researcher, as well as a member of Simmaron’s Scientific Advisory Board.

Proponents of using a more restrictive definition such as the CCC/ICC believe that winnowing out a homogeneous group in research studies could be the key to figuring out ME/CFS. Once ‘non-ME/CFS patients are eliminated, core factor will pop out and be quickly replicated. It’s an enticing vision.

Others worry that a more narrowly focused group might miss some legitimate ME/CFS patients. The ‘wider net’ approach, may have been embodied in the ’empirical definition’, which grabbed a large set of ‘CFS’ patients, from which subsets could conceivably have been winnowed.

This strategy would have the benefit of applying to a larger population (up to 4 million in the US), and might work well if the funds and will had been available. Without that commitment that strategy runs the risk of producing almost meaningless results.

A recent publication by Dr. Sonya Marshall-Gradisnik’s team compares the immune functioning of ME/CFS patients meeting the International Consensus Criteria vs. those meeting the Fukuda/1994 CDC definition, giving us a start on determining the pros and cons of a more narrow vs. a broader approach to ME/CFS research.

Fukuda/1994 CDC Definition

The fact that few research papers in the last twenty years used something other than the 1994 Fukuda definition to define their participants means that virtually all the findings in ME/CFS from the natural killer cell dysfunctions to low blood volume to exercise intolerance, etc., have all been found using the Fukuda definition. By putting all researchers on the same playing field, the Fukuda definition has played an important place in the history of ME/CFS research, but its vagueness and its inability to highlight what many believe to be the key symptom in ME/CFS means it almost certainly allows several questionable subsets into research studies.

The Study

Sixty-three participants including 41 people with ME/CFS and 22 controls answered questionnaires and gave blood samples. The blood samples were assessed for immune functioning. All patients had been previously diagnosed with chronic fatigue syndrome at the National Centre for Neuroimmunology and Emerging Diseases, a top ME/CFS research lab (and soon to be clinic) led by Dr. Sonya Marshall-Gradisnik in Australia. (Dr. Marshall-Gradisnik serves on the Simmaron Research Foundation’s Board).

Results

The breakdown was fascinating. Seventeen people met the Fukuda criteria but not the ICC, and 18 people met both the ICC and the Fukuda criteria. Five people — over 10 percent — of the ME/CFS patients met neither criteria. This was one small study, but it did suggest that a large percentage of people that doctors identify with ‘chronic fatigue syndrome’ may not meet the ICC, and another substantial subset may not meet either criteria. It does not bode well for a more restrictive approach to ME/CFS.

Natural Killer Cells

It was no surprise to see reduced NK cell functioning show up in both the ICC and Fukuda groups. This reduced natural killer cell functioning is believed to inhibit the ME/CFS patient’s ability to clear new infections and/or stop recurring infections. (Interestingly, reduced NK cell function was not associated with alterations in the cytotoxic factors – granzymes and perforin – that NK cells use to kill cells, as has been seen in the past. The authors suggested, however, that this might have been due to the small sample size.)

Immune Suppression Enhanced in the ICC Group

Both groups demonstrated immune suppression, but the immune suppression was significantly increased in the ICC patients. The increased prevalence of two inhibitory or suppressive immune factors in the ICC group suggested a) they were a distinct group, (b) the promise of more abnormalities showing up when a more restrictive definition was used was fulfilled and c) that their immune system was having more trouble than the Fukuda group’s in becoming properly activated. Treg or T regulatory cells or ‘suppressor’ T-cells are rather new to the scene in ME/CFS, but this is the third study showing significant increases in these cells. That suggests they may play an important role in chronic fatigue syndrome. High levels of Treg cells could be suppressing natural killer cell functioning in ME/CFS.

Both groups exhibited reduced immune activity, but more immune suppression was found in the ICC group

KIR Receptors – High levels of ‘KIR’ receptors on the NK cells of the ICC group (but not the CDC group) could further suppress NK cell function. The presence of two ‘profoundly’ inhibiting factors suggested the ICC group’s immune systems were getting particularly hammered. (Increased levels of an ‘activating’ NK cell receptor were also found. The authors felt this resulted from an attempt to balance the ‘overwhelming’ inhibitory signals from the two inhibitory receptors.) (Receptors on the surface of a cell greatly influence what the cell does. NK cells that are dotted with inhibitory receptors, for instance, can be easily turned off. Conversely, NK cells with few inhibitory receptors will be difficult to turn off.) The authors suggested, but could not prove, that the ICC group carried genes that promoted a tendency towards NK inhibition.

Hitting Home – Physical Functioning Affected

One of the vital questions regarding the abnormalities in ME/CFS is how much they matter. Ironically, THE immune finding in ME/CFS, poor NK cell functioning, didn’t pan out in this regard. While low NK cell functioning was associated with poorer health in the healthy controls, it didn’t appear, at least in this small study, to be correlated with poorer health in the ME/CFS groups. Decreased CD39+ and altered KIR receptors were, however, ‘strongly’ associated with poorer health in the ICC (but not the Fukuda delineated patients). This suggested that immune suppression was having an impact in the ICC delineated patients.

Touchy Situation Ahead

The increased amount of immune suppression in the ICC group suggested that the ICC criteria did select a more immune-challenged set of patients and that group should be set apart for separate study. The immune findings in the Fukuda group (low NK cell functioning/increased Tregs) were nothing to sneeze at, however. Plus, the high percentage (almost 50%) of patients meeting the Fukuda criteria, but not the ICC criteria indicated that group cannot be ignored. The ten percent of people with ME/CFS that met neither criteria suggested an important subset of people who are sick, but don’t meet either criteria, may be present. The fact that all the study participants were identified by ME/CFS researchers/doctors working at an ME/CFS lab suggested they were indeed ME/CFS patients. These researchers proposed that both groups should be included in studies. Since all the people that met the ICC also met the Fukuda/1994 CDC criteria, starting off with the Fukuda criteria and then examining the ICC criteria patients could achieve this.

Conclusion

“These findings are highly suggestive of a need to incorporate both the 1994 CDC and the ICC in future clinical research”

Study authors

With a new research definition coming up on the docket, it was good a see a study examining a prominent candidate — the International Consensus Criteria.

With this study suggesting both definitions have merit, determining how wide or narrow of a net to cast in the research definition will not be easy.

The IOM contract for a clinical definition was really just a prelude to the big problem looming ahead, which is creating an appropriate research definition.

Since the research definition defines what types of patients participate in a study, its use can fundamentally alter how a disorder is viewed or researched.

The suppressive nature of the immune dysfunctions found in the ICC group suggested, to my mind, that they might be ‘Fukuda plus’ patients dogged by increased levels of immune suppression.

This study gave no clear answers. It suggested that patients that meet the Fukuda criteria but not the ICC criteria are an important subset of ME/CFS, but it also suggested that segregating patients meeting the ICC criteria could help uncover more immune abnormalities.